IgG4-related disease (IgG4RD) is a fibrotic immune-mediated condition that can affect almost any organ and is now recognized with increasing frequency. It is histologically characterized by a lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate tissue eosinophilia. This diagnosis unifies a spectrum of disorders, previously thought to be separate entities, such as Mikulicz's disease, Kuttner's tumor, Riedel's thyroiditis, autoimmune pancreatitis, Ormond's disease, among others. IgG4 itself is a non-inflammatory immunoglobulin and is unlikely to be directly pathogenic. However, IgG4RD lesions are diffusely infiltrated with CD4+ T cells that are thought to drive fibrosis. Preliminary studies in subjects with IgG4RD, suggests that a novel and potentially pathogenic subset of human CD4+ T cells characterized by the production of an unusual combination of IFN-, IL1- and cytotoxic effector molecules is associated with active disease. The role of these cells in the pathogenesis of IgG4RD will be explored in three specific aims: (1) characterization of expanded disease-associated CD4+ effector T cell subsets, (2) determination of the antigen driving B and T cell expansions in IgG4RD, (3) elucidation of the genetic and molecular mechanisms underlying the fibroinflammatory pathology of IgG4RD lesions. This project and the proposed career development activities will be carried out will be carried out by Dr. Mahajan with guidance from an internationally-renowned group of scientific and clinical mentors with varying and complementary expertise: Dr. Shiv Pillai, Dr. John Stone, Dr. Vijay Kuchroo and Dr. Andrew Luster. Dr. Mahajan received his graduate training in cellular and molecular immunology at MIT and residency training in Clinical Pathology at the Brigham and Women's Hospital (BWH), where he serves as an Associate Pathologist. This Career Development Award will provide Dr. Mahajan with protected time for an intensive career development experience in human translational immunology, wherein he will take full advantage of the expertise of his mentor and scientific advisors as well as attend scientific meetings, seminars, retreats and courses related to his research area and clinical activity. The results of this study on the pathogenesis of IgG4-related disease may be of broad relevance to other fibrotic autoimmune diseases.